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Activated phagocytes express considerable amounts of MRP8 and MRP14, 2 calcium-binding S100 proteins forming stable heterodimers that are specifically secreted at inflammatory sites in many diseases. We previously reported that treatment of human microvascular endothelial cells with purified MRP8/MRP14 leads to loss of endothelial cell contacts. In this study, we demonstrate that MRP8/MRP14 complexes furthermore trigger cell death of endothelial cells after the onset of cell detachment. Morphologic analysis of dying endothelial cells revealed characteristic features of both apoptosis and necrosis. Furthermore, MRP8/MRP14 induced apoptotic caspase-9 and caspase-3 activation, DNA fragmentation, and membrane phosphatidylserine exposure in target cells. These events were independent of death receptor signaling and in part controlled by a mitochondrial pathway. Consistently, overexpression of antiapoptotic Bcl-2 abrogated caspase activation and externalization of phosphatidylserine; however, MRP8/MRP14 still induced plasma membrane damage and even DNA fragmentation. Thus, our results demonstrate that MRP8/MRP14 triggers cell death via caspase-dependent as well as -independent mechanisms. Excessive release of cytotoxic MRP8/MRP14 by activated phagocytes might therefore present an important molecular pathomechanism contributing to endothelial damage during vasculitis and other inflammatory diseases.